Schizophrenia is a frequent and disabling disease of variable expression and unknown etiology, with the majority of cases having an onset before age 45. Both cognitive and emotional dysfunction is observed causing social and occupational impairment. There is convincing evidence that genetic susceptibility plays some role in determining who is affected. Like most common complex diseases, it is likely that mutations at several or many different loci are associated with susceptibility.Since 1983 our group has focused on the epidemiologic and genetic study of schizophrenia and other psychotic disorders. We have developed several clinical samples including multiplex pedigrees with schizophrenia. These families have been examined in a series of investigations including linkage studies that have provided evidence for schizophrenia susceptibility loci on chromosomes 8, 13 and 22. Other groups have supported these findings. Individuals in these families were last seen during the period 1989-1995. There are undoubtedly individuals in these families who have since developed schizophrenia.The long term objective of this research is to localize and characterize genes of importance to schizophrenia and to test the hypothesis that some genetically-determined susceptibility is associated with identifiable subgroups of the patients. This application requests support to update the clinical status of individuals in our large, already-established multiplex families, to replenish our supply of DNA from lymphoblastoid cell lines and to conduct state of the art analyses of previously obtained molecular data as well as the new data that will be generated during this grant period (i.e., linkage analysis, linkage disequilibrium studies, and haplotype relative risk studies, using highly polymorphic microsatellite markers and anonymous and candidate SNP's). No support is necessary for this molecular genetics laboratory work. For this initial grant period, laboratory efforts will focus on identifying a susceptibility gene on chromosome 8. Understanding the factors that contribute to schizophrenia may benefit affected individuals and their relatives, Identification of the genes involved may provide new targets for the development of medications to ameliorate these disorders.